Kessel1 Flashcards
Properties of malignant cells
evade apoptosis, self sufficiency in growth signals, insensitivity to anti growth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis
Why use chemotherapy?
precise sites of neoplasia can be difficult to detect. need to seek out and eradicate.
What are the major classes of drugs for cancer?
antimetabolites (inhibit DNA syn)
Alkylating agents (impair DNA fxn)
Antibiotics (DNA binders)
Hormone antagonists (inhib receptor fxn)
How does methotrexate function?
Blocks the transfer of 1 carbon fragment from Uracil to thymine. DNA synthesis STOPS.. Inhibits the enzyme dihydrofoilic reductase
antagonizes the synthesis of thymidyic acid, precursor of dna
Resistance of 5FU looks at what?
impaired transport system! selection for tumor cell with high DHFR levels
What is an example of an S-phase specific drug? how does it function?
Cytosine arabinoside (Ara-C) incorporated into DNA,terminates DNA chain elongation,inhibits DNA polymerase
Gemcitabine specs
Targets G0/G1 cells–accum of S phase cells.
Incorporated into DNA + inhibits ribonucleotide reductase
Alkylating agents preferentially attack?
DNA guanines- cross link impair strand separation and DNA/RNA synthesis is impaired. Response increase by lack of repair enzymes
How can we circumvent MTX toxicity?
supply a cell with folinic acid, a reduced folate
5-FU is enzymatically modified to its functional form…?
FUdRP- potent inhibitor of thymidylate synthesis
What are the components of the triple complex that inhibits enzyme function?
FUdRP, reduced folate, enzyme thymidylate synthetase
FU is inactivated by WHAT
the enzyme DPD! dihydropyridinede hydrogenase
In general, how do the alkylating agents function?
Agents transformed into highly reactive structures toward all nucelophilic groups. Alkylated DNA cannot function properly during replication, synthesis inhibited. Treatslowly-dividing cancer cellsunresponisble to antimetabolites.
What is nitrogenmustard (HN2)
A very powerful alkylating everything.Alykates sites onseparate strandsofDNA,cross-linking DNA strands. cannot replicate! TWoothers: mlphalan, chlorambucil!takenorally and broader spectrum.
Benefits of Cyclophosphamide
Broad spectrum,given orally (require activation by liver enzymes)
MESNA
drug that can neutralize the inflammatory drug metabolites of CTX that concentrate in the bladder
How does temolozolomide work???
Once activated, the product can be mistaken for adenine! so, base-pair mismatching! eventual los of viability
Cis Platinom MOA
after loss of thechlorineatoms, drug acts similar to alkylating agent, covalent bondwithaminoresidues ofucleic acids. littlecell-cycle specificity.
DNA crosslinker, renalexcretion, can cause hearing loss, limitingtox: renal! distortion of the DNA strandcaused by binding of amolcule of cisPT notrecognizined by DNA repair enzymes in malignant cell lines. permaenent damage and todna replication andcelldeath.
Drug resistance patterns
- decreased entry into orincreased loss from cell.
- drug inactivated within cell
- enhanced DNA repair after alkylation
Actinomycin D
antibiotic that bindstightly toDNA,inhibitingRNAsynthesis.No covalent bonds withDNA but fitsINTOa portionofthehelicalstrucutre(INTERCALATION)
Bleomycin
Results in breakin gand fragmentation of theDNA strands! drug concentratesinskinand lung, no marrow toxicity.
Doxorubicin
binds to DNA,inhibits subsequent synthesis. can also bind tonondefinng andpromote cell death inhibit cellviability via interactions with topoisomerase II.
ANthracycins!
bnefit! doxorubicin! broad spectrum efiacy. tox BM and heart muscle. Cardic muscle toxicity!! FREE RADICALS!!
VINCA alkaloids!
arrest cell division at metaphase by disrupting microtubule structures. Also neural MT- neurotox.
Taxol
promotes tubulin polymerization and stability of MT… (vincas promotemicrotubule dissociation) Inhibit metaphase and mitosis! Chemotherapy additive disables side effect.
Camptothecin
Topoisomerase I antagonist
Etoposide
Topoisomerase II inhibitor. tox to GI tract and bone marrow
Multidrug resistance
transport system that pumps drugs out of cells! protective to normal cell types. missing in malignant cells.
Gleevec (imitinib)
SO HELPFUL for CML!! interrupts the phosphyrlation of several substrates that activate growth signals
Monoclonals
Erbitux-targets egrf
avastin- targets vegf
Herceptin targets her2neu
Cytotoxic action of MTX antagonized by ?
combination of thymidine and folinic acid!
How can MTX possibly antagonize 5FU?
ohhhhhh you know, MTX limits folinic acid production. necessary for 5FU’s triple complex
5FU resistance is caused by WHAT?
TUMOR CELL DELETES ONE OR MORE ENZYMES INVOLVED IN THE PHOSPORYLATION OF FU
